F2‐03‐04: Circadian patterns of beta‐amyloid in human cerebrospinal fluid and plasma

Abstract

The amyloid hypothesis predicts that increased production or decreased clearance of amyloid-beta (Aβ) leads to amyloidosis, which ultimately culminates in Alzheimer's disease (AD). Changes in amyloid proteins, such as decreased cerebrospinal fluid (CSF) Aβ42 have been recognized as a biomarker for AD. However, the dynamics of Aβ concentrations over time are not well understood. Hourly CSF and plasma samples were obtained over a 36-hour study period in three groups of human volunteers: a dementia group with amyloid deposition, an age-matched control group, and a younger control group. We investigated dynamic patterns of Aβ peptides (Aβ40 and Aβ42 in CSF and plasma using bead-based Luminex XMAP assays), and Amyloid Precursor Protein (APP) (APP-α and APP-β in CSF using ELISA assays). We then analyzed the effects of aging and amyloidosis on circadian patterns and correlations between CSF and plasma Aβ peptides. Circadian patterns were observed in CSF and plasma Aβ, with decreased amplitudes with aging. Further, CSF APP also demonstrated a circadian pattern. No significant correlations were found between plasma and CSF Aβ levels on an hourly or individual basis. We also found that CSF APPα, APPβ, Aβ40, and Aβ42 are highly positively correlated in all participants without amyloidosis. However, in participants with amyloidosis, there is no correlation of Aβ42 to the other APP metabolites, suggesting that normal physiologic regulation of CSF Aβ42 is impaired in the presence of amyloidosis. This study suggests amyloid proteins in both central and peripheral compartments are dynamic, and regulated in a circadian pattern that is part of the normal dynamic physiologic control of Aβ concentrations. Regulatory mechanisms of these proteins may be altered with aging and amyloidosis. The lack of correlation of plasma and CSF Aβ levels suggest plasma Aβ concentrations can not be used for surrogates of central Aβ concentrations. These findings support an active circadian regulation of Aβ and may provide insight into the pathophysiological changes in AD.